{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:31Z","timestamp":1787028571880,"version":"build-2736575974"},"reference-count":97,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T00:00:00Z","timestamp":1761264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Breast cancer remains a major global health challenge. In 2022, there were an estimated 2.3 million new cases and 670,000 deaths among women worldwide. Hormone receptor-positive (HR+)\/human epidermal growth factor receptor 2-negative (HER2\u2212) breast cancer accounts for approximately 70% of breast cancer diagnoses. The treatment landscape for advanced HR+)\/HER2\u2212 breast cancer has been transformed by the introduction of CDK4\/6 inhibitors in the first-line setting. However, therapeutic strategies following progression on CDK4\/6 inhibitors remain heterogeneous and uncertainty exists in their optimal integration in clinical practice. This review aims to systematically examine available second-line and subsequent treatment options for HR+\/HER2\u2212 metastatic breast cancer after progression on CDK4\/6 inhibitors, with a focus on biomarker-driven strategies and emerging therapies. The therapeutic landscape beyond CDK4\/6 inhibitors includes targeted agents guided by actionable biomarkers as well as novel selective estrogen receptor degraders (SERDs). In biomarker-unselected populations, options include CDK4\/6 continuation strategies, endocrine monotherapy in selected cases, and cytotoxic therapy. The integration of molecular testing via next-generation sequencing has become standard of care in guiding these decisions. However, overlapping molecular alterations and a lack of consensus on treatment sequencing pose significant challenges. Prognostic factors such as circulating tumor DNA dynamics may further refine treatment personalization. Post-CDK4\/6 therapy in HR+\/HER2\u2212 metastatic breast cancer is an evolving and increasingly complex area of practice. Optimal treatment selection should be tailored to both tumor biology and patient-specific factors, supported by molecular testing and high-quality evidence.<\/jats:p>","DOI":"10.3390\/ijms262110366","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:51:42Z","timestamp":1761526302000},"page":"10366","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Navigating Treatment Sequencing in Advanced HR+\/HER2\u2212 Breast Cancer After CDK4\/6 Inhibitors: Biomarker-Driven Strategies and Emerging Therapies"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4208-8827","authenticated-orcid":false,"given":"Dana P.","family":"Narvaez","sequence":"first","affiliation":[{"name":"Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1080-0998","authenticated-orcid":false,"given":"David W.","family":"Cescon","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1016\/j.breast.2022.02.003","article-title":"Global challenges in breast cancer detection and treatment","volume":"62","author":"Barrios","year":"2022","journal-title":"Breast"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1177\/08465371241246422","article-title":"Incidence of Breast Cancer in Younger Women: A Canadian Trend Analysis","volume":"75","author":"Seely","year":"2024","journal-title":"Can. 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